N-methyl-imidazole derivatives and their production

ABSTRACT

N-methyl-imidazole derivatives of the formula:   OR A PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALT THEREOF, WHEREIN X is an unsubstituted or substituted 6-membered hetero-aromatic moiety having two nitro heteroatoms, Y is an unsubstituted or substituted aliphatic moiety, an unsubstituted or substituted cycloaliphatic moiety, an unsubstituted or substituted aralkyl moiety or an unsubstituted or substituted aryl moiety, and Z is an unsubstituted or substituted aliphatic moiety, an unsubstituted or substituted cycloaliphatic moiety, an unsubstituted or substituted aralkyl moiety, an unsubstituted or substituted aryl moiety, an unsubstituted or substituted pyridyl moiety or an alkoxycarbonyl moiety, ARE USEFUL AS ANTIMYCOTIC AGENTS.

United States Patent [191 Draber et al.

[ N-METHYL-IMIDAZOLE DERIVATIVES AND THEIR PRODUCTION [75] Inventors: Wilfried Draber; Karl Heinz Biichel; Erik Regel; Manfred Plempel, all of Wuppertal-Elberfeld, Germany [73] Assignee: Bayer Aktiengesellschaft, Germany [22] Filed: Nov. 29, 1972 [21] Appl. No.: 310,400

Related US. Application Data [62] Division of Ser. No. 120,333, March 2, 1971, Pat.

[30] Foreign Application Priority Data Mar. 23, 1970 Germany 2013793 [52] US. Cl... 260/250 A; 260/250 AH; 260/250 R; 260/251 R; 260/256.4 C; 260/256.4 R; 260/309; 424/250; 424/251 Dec. 23, 1975 Primary Examiner-Pau1 M. Coughlan, Jr. Assistant Examiner-James H. Turnipseed [57] ABSTRACT N-methyl-imidazole derivatives of the formula:

Y-C-N/\N (I) or a pharmaceutically acceptable non-toxic salt thereof, 9 wherein X is an unsubstituted or substituted o-membered hetero-aromatic moiety having two nitro heteroatoms, Y is an unsubstituted or substituted aliphatic moiety, an unsubstituted or substituted cycloaliphatic moiety, an unsubstituted or substituted aralkyl moiety or an unsubstituted or substituted aryl moiety, and Z is an unsubstituted or substituted aliphatic moiety, an unsubstituted or substituted cycloaliphatic moiety, an unsubstituted or substituted aralkyl moiety, an unsubstituted or substituted aryl moiety, an unsubstituted or substituted pyridyl moiety or an alkoxycarbonyl moiety, are useful as antimycotic agents.

7 Claims, N0 Drawings N-METHYL-IMIDAZOLE DERIVATIVES THEIR PRODUCTION which are bonded to the central carbon atom of formula (1) via a carbon atom in the ring and can either be unsubstituted or may be substituted by l to 3, and

This is a division of application 5 preferably 1 or 2 substituents which can either be the filed Mar. 2, 1971, now US. Pat. No. 3,787,415, issued Jan. 22, 1974.

The present invention is concerned with N-methylimidazole derivatives and their production as well as with pharmaceutical compositions, wherein said N- methyl-imidazole derivatives are the active ingredient and with methods of treating mycotic infections which comprises administering the N-methyl-imidazole derivatives of the present invention.

More particularly, the present invention is concerned with N-methyl-imidazole derivatives which are substituted at. the methyl carbon atom by a G-membered heterocyclic moiety having two ring nitrogen atoms. These compounds are particularly useful for their antimycotic and fungitoxic activity.

Some derivatives of 6-membered heterocyclic compounds, which contain two nitrogen atoms in the nucleus, are known. US. Pat. No. 2,839,446 describes pyrimidies which carry a trichloromethylsulphonyl group in the 2-position as being leaf fungicides. Netherlands Patent No. 6,806,106 describes S-substituted pyrimidines carrying a disubstituted or trisubstituted methyl group as the substituent, it being possible for one of the substituents on this methyl group to be a hydroxyl, amino or phenylamino group. The pyrimidyldiaryl-carbinols, in particular, represent valuable systematic plant fungicides. These previously known compounds are however all exclusively active against plantpathogenic fungi and bacteria.

N-trityl-imidazole and substituted N-trityl-imidazoles are referred to in U.S. Pat. No. 3,321,366 as being useful against plant fungi.

The compounds of the present invention may be represented bythe formula:

z I -c- /\N (1) wherein X is an unsubstituted or substituted 6-membered heteroaromatic moiety having two nitro heteroatoms,

Y is an unsubstituted or-substituted aliphatic moiety, an unsubstituted or substituted cycloaliphatic moiety, an unsubstituted or substituted aralkyl moiety or an unsubstituted or substituted aryl moiety, and

and {1 same or different. Suitable substituents include halogen, particularly fluorine, chlorine and bromine, and especially chlorine, alkyl of l to 4 carbon atoms, and preferably 1 or 2 carbon atoms, alkoxy of l to 4 carbon atoms, and preferably 1 or 2 carbon atoms or phenyl. Among the above alkyl and alkoxy substituents are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. butyl, particularly methyl and ethyl, and methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy 5 and tert. butoxy, especially methoxy and ethoxy. If X is a pyridazine ring, it is preferably bonded in the 4-position to the central carbon atom. If R is a pyrimidine ring, it is preferred that it be bonded in the 2- or 5-position to the central carbon atom.

When Y and/or Z are unsubstituted or substituted aliphatic moieties, it is preferred that such aliphatic moieties be straight-or branched chain alkyl of l to 6 carbon atoms, and especially 1 to 4 carbon atoms, particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl and tert. butyl, particularly methyl and tert. butyl. When such aliphatic moieties are substituted, it is preferred that there be one or more substituents, and preferably one or two substituents. Suitable substituents are alkyl of l to 4 carbon atoms, and preferably 1 or 2 carbon atoms, alkoxy of l to 4 carbon atoms, and preferably 1 or 2 carbon atoms,thioalkyl of 1 to 4 carbon atoms, and preferably 1 or 2 carbon atoms, trifluoromethyl, halogen, especially fluorine, chlorine or bromine, nitro and cyano. Particular alkyl, alkoxy and thioalkyl moieties include methyl, ethyl, methoxy, ethoxy, methylmercapto, i.e. thiomethyl and ethylmercapto, i.e. thioethyl.

When X- and/or Z are unsubstituted or substituted cycloaliphatic moieties, it is preferred that these have 3 to 8 carbon atoms, and especially 3 to 6 carbon atoms. Cyclopropyl and cyclohexyl are preferred moieties. When the cycloaliphatic moieties are substituted, it is preferred that there are one or more substituents and preferably one or two substituents. Suitable substituents include alkyl of l to 4 carbon atoms, preferably 1 or 2 carbon atoms, alkoxy of l to 4 carbon atoms, preferably 1 or 2 carbon atoms, thioalkyl of l to 4 carbon atoms, preferably 1 or 2 carbon atoms, trifluoromethyl, halogen, especially fluorine, chlorine or bromine, nitro and cyano. Among the alkyl, alkoxy and thialkyl moieties are methyl, ethyl, methoxy, ethoxy, methylmercapto and ethylmercapto.

When Y and/or Z are unsubstituted or substituted aralkyl moieties, it is preferred that these have 6 to 12 carbon atoms, and especially 6 carbon atoms in the aryl portion, and 1 to 4 carbon atoms, and especially 1 or 2 carbon atoms in the alkyl portion. Benzyl and p-chlorobenzyl are among the preferred substituents. When the aralkyl moiety is substituted, there can be one or more substituents, preferably one or two. Substituents include alkyl of 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, alkoxy of l to 4 carbon atoms, preferably l or 2 carbon atoms, thioalkyl of l to 4 carbon atoms, preferably 1 or 2 carbon atoms, trifluoromethyl,

halogen, especially fluorine, chlorine or bromine, nitro and cyano. Among the alkyl, alkoxy and thialkyl moieties are methyl, ethyl, methoxy, ethoxy, methylmercapto and ethylmercapto.

When Y and/or Z are unsubstituted or substituted aryl moieties, it is preferred that these have 6 to 10 carbon atoms, and especially 6 carbon atoms. When the aryl moiety is substituted, there can be one or more substituents, preferably 1 or 2. Substituents include alkyl of l to 4 carbon atoms, preferably 1 or 2 carbon atoms, alkoxy of 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, thioalkyl of 1 to 4 carbon atoms, preferably l or 2 carbon atoms, trifluoromethyl, halogen, especially fluorine, chlorine or bromine, nitro and cyano. Among the alkyl, alkoxy and thioalkyl moieties are methyl, ethyl, methoxy, ethoxy, methylmercapto and ethylmercapto.

The preferred aryl moieties are phenyl, p-fluorophenyl, o-chlorophenyl, o-methylphenyl, o-isopropylphenyl, p-methoxyphenyl, m-trifluoromethylphenyl, mnitrophenyl and naphthyl.

When Z is an unsubstituted or substituted pyridyl' moiety, the pyridyl moiety is bonded in the 2-, 3- or 4-position to the central carbon atom. When the pyridyl moiety is substituted, it can contain one or more substituents, and preferably 1 or 2 substituents. Suitable substituents include alkyl of 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, alkoxy of l to 4 carbon atoms, preferably 1 or 2 carbon atoms, thioalkyl of 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, trifluoromethyl halogen, especially fluorine, chlorine and bromine, nitro and cyano. Among the alkyl, alkoxy and thioalkyl moieties are methyl, ethyl, methoxy, ethoxy, methylmercapto and ethylmercapto. When Z is pyridyl, it is preferred that the pyridyl moiety be unsubstituted.

When Z is alkoxycarbonyl, it is preferred that there be 1 to 4 carbon atoms, and especially 1 or 2 carbon atoms, in the alkyl moiety. Methoxycarbonyl and ethoxycarbonyl are preferred.

Preferred salts of the compounds of the present invention are those which are formed with pharmaceutically acceptable non-toxic acids, i.e. those which are physiologically well tolerated. Examples of such acids are the hydrogen halide acids, such as for example hydrobromic acid and hydrochloric acid, phosphoric acids, sulphonic acids, monocarboxylic and dicarboxylic acids and hydroxycarboxylic acids. As examples of organic acids, acetic acid, tartaric acid, lactic acid, malic acid, citric acid, salicylic acid, sorbic acid and ascorbic acid may be mentioned.

Particularly preferred compounds are those of the formula (I) in which X is a 6-membered heteroaromatic ring of the formula:

l NAN a. a compound of the formula Y- Hal (ll) wherein X, Y and Z are as above defined, and

Hal is Cl or Br, is reacted with imidazole, optionally in the presence of an acid acceptor or in the presence of an excess of imidazole in a polar organic solvent at temperatures between about 20 and about 150 C, and the salt is optionally manufactured, or

b. a carbinol of the formula:

Y-- --OH wherein X, Y and Z are as above defined, is reacted with thionyldiimidazole of formula in an aprotic solvent, and the salt is optionally manufactured.

The starting compounds required for the manufacture of the new compounds (I) are known or are obtainable according to known processes.

The compounds (ll) can be manufactured in various ways. For example, it is possible to start from a carbinol (HI) and to react this with a halogenating agent, such as for example thionyl chloride, thionyl bromide, phosphoryl chloride, phosphoryl bromide, acetyl chloride or acetyl bromide, in solvents, such as for example ether, methylene chloride, benzene or toluene. If may at times also be appropriate to carry out the halogenation in a polar solvent and to follow this directly by the reaction with imidazole, without intermediate isolation of the halide formed. As polar organic solvents, acetonitrile nitromethane, dimethylformamide or hexamethylphosphoric acid triamide may for example be mentioned.

A further process for the manufacture of. compounds of the formula (ll), in which Hal is chlorine and X and Y are as above defined, comprises reacting a ketone of the formula:

x-i v v X- Y (VI) wherein X and Y are as above defined. This dichloride is subsequently reacted with an optionally substituted equivalent of aluminium chloride, to give the chloride An excess of the aromatic compound, or some other solvent suitable for this reaction, such as for example carbon disulphide, can be used as the solvent in this Friedel-Crafts reaction.

A further process for the manufacture of the halides (II) consists of reacting a methane derivative of the formula (VII) in which X, Y and Z have the abovementioned meanindicated are known or can be manufactured analogously to known processes. For example, 2-diphenylmethylpyrazine is obtained according to a method described by Behun et al, J. Org. Chem. 26, 3379 (1961 Further pyrazylcarbinols have been described by Hirschberg, J. Heterocyclic Chem. 2, 209 (1965). Further, pyrazine derivatives which can be used as starting substances of general formulae (II), (III) and (VII), in

which X represents a pyrazine radical, for the manufacture of compounds of formula (I), in which X is a pyrazine radical, are described in Netherlands Patent No. 105,432 and in German Displayed Specification No. 1,913,726.

Pyrimidine compounds of the formula (II), (III) and (VII), in which X is pyrimidine, used as starting substances, are also known or can be manufactured accord ng to processes which arein themselves known.

a cH

Several processes are for example given in Chem. Ber. 93, 230 (19.60) and in Netherlands Patent Application No. 6,806,106.

Pyridazine compounds of the formula (II), (III) and (VII), in which X is pyridazine, can also be obtained in an analogous mannerto that described in the abovementioned publications.

In process variant (a)the starting compound (II), the imidazole and the acid acceptor are employed in about molar'amounts. If an excess ofimidazole is added as the acid acceptor, about 2 mols of imidazole must be used for this reaction. The reaction temperature is about 20 to about 150C, preferably about to about C.

As solvents in process (a), polar organic solvents, such as for example lower alkylnitriles, such as for example acetonitrile, dimethylformamide, dimethylsulphoxide, lower alkylketones, such as for example diethyl ketone, and hexamethyl phosphoric acid triamide can be used.

Inorganic and organic bases can serve as acid acceptors. As inorganic bases, the alkali carbonates and alkaline earth-carbonates, especially potassium carbonate and calcium carbonate, may for example be used. As organic bases, lower alkylamines, such as for example triethylamine, as well as hetero-aromatic bases, such as for example pyridine and lutidine may for example be used. 1

In process variant (b), the reactants (III) and ('IV)' are employed in about molar amounts. Preferably, however, about 1 to about 2 'mols of thionyldiimidazole (IV) are employed per '1 mol ofcarbinol '(III); The

reaction temperature is about 0. to about 100C, preferably about20to about 50C. The reaction -,(b) is generally carried out in ine organic solvents, such as for example lower alkylnitriles, suchas for example acetonitrile, ethers, such as for example tetrahydrofurane and diisopropyl ether, 1 dimethylformamide or chlorinated hydrocarbons, such as for example chloroform.

If 2-isopropyl-phenyl-2-pyrazyl-carbinol is used as the starting material, the course of the reaction according to process (a) can be represented by the following equation:

The course of reaction of process (b) can be represented by the following equation for the example of the reaction of tert.-butyl-phenyl--pyrimidyl-carbinol with thionyldiimidazole:

c-ca -soare obtained, which after recrystallisation from etherlacetone yield 8.8 g (28 of theory) of a compound of the formula in the form of white crystals of melting point 198C.

Analysis: C H N (312.36). Calculated: C, 76.9% I H,5.2% N, 17.9%. F0und:C,76.9% H,5.5% N, 18.0%.

EXAMPLE 3 4-Fluorophenyl-phenyl-pyrazyl-imidazol- 1 -yl-methane 28.0 g (0.1 mol) of 4-fiuorophenyl-phenyl-pyrazylcarbinol together with a solution of 0. l 5 mol of thionyldiimidazole in 200 ml of acetonitrile are heated to the boil for 1 hour. Thereafter the mixture is filtered and concentrated, the residue is taken up in methylene chloride and the solution is repeatedly extracted by shaking with water. The methylene chloride phase is dried and concentrated. A brown oil is obtained, which The following non-limitative examples more particularly illustrate the present invention.

EXAMPLE 1 Diphenyl-pyrimid-S-yl-imidazol-l-yl-methane.

26.2 g (0.1 mole) of diphenyl-pyrimid-S-yl-carbinol, melting point 161C, are treated with a solution of 0. 1 5 mol of thionyldiimidazole in 200 ml of dry acetonitrile 35 and the mixture is heated to the boil for 10 minutes. Thereafter it is cooled, diluted with ice water and filtered. The residue is washed with water. 23.6 g (76% of theory) of a white, finely crystalline substance of formula 40 of melting point 209C are obtained.

Analysis: C l-l N (312.36). Calculated C, 76.9% H, 5.2% N, 17.9%. Found: C, 77.3% H, 5.6% N, 18.0%.

The thionyldiimidazole used for the reaction is obtainable as follows:

is taken up in acetonitrile. After treating the solution with active charcoal and filtering, dry hydrogen chloride is passed in until saturation is reached, and the precipitated product is filtered off and rinsed with ace- 40.8 g (0.6 mol) of imidazole dried over P 0 are tonitrile and ether. 12.7 g (35% of theory) of the comsuspended in ml of acetonitrile distilled over P 0 and treated, at 0C, with 17.7 g (0.15 mol) of freshly distilled thionyl chloride. The imidazole hydrochloride. which has precipitated is rapidly filtered off and rinsed with 50 ml of acetonitrile. The filtrate is immediately 5 used for the reaction.

EXAMPLE 2 Diphenyl-pyrazyl-imidazol-l -yl-methane.

26.2 g (0.1 mol) of diphenyl-pyrazyl-carbinol, melting point 1 l 1C, are treated with a solution of 0.15 mol pound of formula HCl Analysis: C H FN HCl (366.81). Calculated: N,

15.3% C1, 9.7%. Found: N, 14.8% Cl, 9.9%.

EXAMPLE 4 Diphenyl-4,5,6-trich1oropyrimid-2-yl-imidazol-1-ylmethane 34.0 g (0.1 mol) of diphenyl-4,5,6-trichloropyrimid- 2-yl-chloromethane in 250 ml of absolute acetonitrile are stirred with 13.6 g (0.2 mol) of imidazole for 3 hours at room temperature and thereafter heated to the boil for 15 minutes. The mixture is then concentrated and the dark brown residue is washed with water and taken up in methylene chloride. After drying with sodium sulphate, treating with active charcoal and filtering, the solution is concentrated. The residue is extracted by boiling with petroleum ether, and the mixture is filtered and again concentrated. Finally, the material is recrystallised from a little acetonitrile. 17.0 g (40% of theory) of the compound of formula Example No are obtained in the form of orange-coloured crystals of melting point 142 146 C.

EXAMPLE 5 Diphenyl-pyrimid-Z-yl-imidazo1- l -yl-methane 26.2 g (0.1 mol) of diphenyl-pyrymid-Z-yI-carbinol are dissolved in ml of absolute acetonitrile and treated with a solution of 0.15 mol of thionyldiimidazole in 200 m1 of acetonitrile. The mixture is stirred for 1 hour at room temperature and subsequently heated to the boil for 10 minutes. It is then concentrated to about half its volume and diluted with ice water. The yellow oil which has precipitated is washed with water, taken up in methylene chloride and the solution dried. After concentration, a viscous residue remains which slowly crystallises. 16.0 g (41% of theory) of the compound of formula are thus obtained, having a melting point of 138 143 C below set forth formula are as indicated, are produced in a manner analogous to that of the preceding examples from the reactants set forth in the table which follows:

HQ Q

The following compounds, wherein X, Y and Z of the Continued Example No. X Y Z Example No Continued Table ple process a) (see pages 7-8) reactants:

( l 4- A N I process b) (see pages 7-8) reactants:

(r neaning of x.Y,z for each example see pages 17-19) Minimal inhibitory concentration (MIC) in 7 ml of substrate Com- Tricho- Micro- Candida Asper- Penicillium pound phyton sporon albicans gillus commune from mentafelineum niger example grophytex 2 4 10 4O 1O 40 l 4 40 4O 10 100 3 l 4 4 4 4 The MIC determination was carried out in a serial dilution test, in the dilution series 100-40-20-10-4-1 'y/ml of substrate. The following were used as nutrient substrates:

a. for Dermatophytes: Sabourauds test medium b. for yeasts: meat water glucose bouillon.

The incubation temperature was 28 C, and the incubation time was 24 to 96 hours.

The preparations are primarily fungistatic: fungicidal effects can be achieved in vitro with 4-fold to 6-fold higher MIC concentrations.

The in vitro experiments were also carried out with the compounds from example 1, 2 and 3, which can be regarded as representative of the entire class of compounds.

b. Anti-mycotic action in vivo.

1. Experimental canidosis in mice.

White mice strain CP -SPF, pellet fodder, water ad libitum were each intravenously infected with l 5 X Candida albicans cells. Untreated control animals died 3 to 6 days after infection to the extent of 95% from uraemia through multiple abscess formation in the kidneys.

In the case of oral and/or parenteral therapy with the preparations mentioned especially with the compound from example 3 in daily doses of 50 to 200 mg/kg of body weight, divided into two individual doses, 60 to 90% of the animals survived on the 6th day after the infection. In these experiments, the therapy was started on the day of the infection and continued up to the 5th day after infection.

The preparations are rapidly resorbed after oral administration. Blood level maxima, with concentrations of up to 6 'y/mg of serum, are reached 4 to 5 hours after administration.

2. Experimental trichophytia in mice, caused by Trichophyton quinckaenum.

White CF,-SPF mice were infected dorsally with a spore suspension of Trichophyton Quinckeanum. After 8 to 10 days typical, multiple cups developed in the untreated control animals.

By means of daily doses of 50 to 200 mg/kg of body weight, divided into two individual doses and administered orally from the day of infection up to the 8th day after infection, it was possible completely to suppress the occurrence of the cups typical of the infection in infected animals.

3. Experimental trichophytia in guinea pigs caused by Trichophyton mentagrophytes.

Guinea pigs Pearlbright white, weighing 400 to 500 g, were infected on their shaved back with a spore suspension of Trichophyton mentagrophytes. A deep dermatomycosis developed at the point of infection within 21 to 25 days, and continued up to the 30th 34th day after infection.

In the case of animals which were treated locally with a 1% strength solution of the preparations in polyethylene glycol 400, once daily from the 3rd day after infection to the 14th day after infection, the infection completely healed within the therapy time. Non-tolerance reactions by the skin were not observable in these ex periments.

According to these results, the preparations mentioned can be regarded as good anti-mycotic agents of broad activity, which are curatively active both in oral and parenteral administration and in local administra tion in animal experiments.

The excellent anti-mycotic activity of the new compounds makes it possible to employ them in the whole of human medicine and veterinary medicine.

The following are envisaged as indications for the new preparations:

1. In human medicine: Dermatomycoses by Dermatophytes, for example varieties of Trichophyton, Microsporon and Epidermophyton, systemic and organic mycoses by, for example, varieties of Candida, Histoplasma, Cryptococcus and Coccidioides, Aspergilli and other moulds.

In veterinary medicine: Dermatomycoses as well as organic mycoses and systemic mycoses caused by Dermatophytes, yeasts, biphase fungi and moulds.

The new compounds can be administered orally, parenterally or locally, as free bases or in the form of their salts with physiologically tolerated acids.

In general, it hasprovedadvantageous to administer amounts of about 30 mg to about 200 mg, preferably about 50 to mg, per kg of body weight per day, to achieve effective results. Nevertheless it can at times be necessary to deviate from the amounts mentioned, in particular depending on the body weight of the test animal or patient, the nature of the method of administration, and severity of the condition as well as because of the species of animal and its individual behavior towards the medicine, or the patients past medical history, or the nature of the formulation and the point in time or interval at which the administration takes place. Thus it can suffice in some cases to use less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the day. The same dosage range is envisaged for administration in human medicine. The other comments made above also apply, in a general sense.

The compounds of the present invention may be formulated into pharmaceutical compositions which comprise a compound according to the present invention in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier. Possible forms for administration, in combination with various inert excipients, are tablets, capsules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such excipients include solid diluents or fillers, a sterile aqueous medium and also various non-toxic organic solvents and the like. Of course the tablets and the like considered for oral administration can be provided with a sweetener additive and the like. The therapeutically active compound should, in the abovementioned case, be present at a concentration of about 0.5 to 90 per cent by weight of the total mixture, that is to say in amounts which suffice to achieve the abovementioned dosage range.

In the case of oral use, tablets can of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additional substances, such as starch, preferably potato starch and the like, and binders such as polyvinylpyrrolidone, gelatines and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulphate and talc can be conjointly used for tablet-making. In the case of aqueous suspensions and/or elixirs which are intended for oral uses, the active substance can be used together with various flavour-improving agents, dyestuffs and emulsifiers and/or together with diluents such as water, ethanol, propylene glycol or glycerine and similar compounds or combinations of this nature.

In the case of parenteral use, solutions of the active substances in sesame oil or groundnut oil or in aqueous propylene glycol of N,N-dimethylformamide can be employed, as can sterile aqueous solutions in the case of the water-soluble compounds. Such aqueous solutions should be buffered in the usual manner where required, and furthermore the liquid diluent should beforehand be rendered isotonic by addition of the requisite amount of salt or glucose. Such aqueous solutions are in particular suitable for intravenous, intramuscular and interperitoneal injections.

The manufacture of such sterile aqueous media is carried out in a known manner.

The compounds are used locally in the form of 0.5 to strength, preferably 1% strength, solutions (for example in dimethylformamide, glycerine or water, alcohol such as ethanol and isopropanol, and buffer solutions), but also as emulsions, suspensions, powders and tablets.

In general, therefore, the invention also provides a pharmaceutical composition comprising as active ingredient at least one of the new active compounds in admixture with a pharmaceutically acceptable nontoxic inert solid or liquid diluent or carrier.

The invention further provides a medicament in unit dosage form comprising as active ingredient at least one of the new active compounds either alone or in admixture with a pharmaceutically acceptable nontoxic inert solid or liquid diluent or carrier. The medicament may include a protective envelope containing the active compound and, if used, the diluent or carrier.

The term medicament in unit dosage form as used in the present specification means a medicament as defined above in the form of discrete portions each containing a unit dose, or a multiple or sub-multiple of a unit dose of the active compound or compounds, especially a half, a third or a quarter of a unit dose, or two, three or four unit doses. Such portions may, for example, be in monolithic coherent from, such as tablets, suppositories, pills or dragees; in wrapped or concealed form, such as wrapped powders, cachets, sachets, or capsules; in ampoules, either free or as a sterile solution suitable for parenteral injection; or in any other form known to the art.

What is claimed is:

1. A compound of the formula:

z ZE ki l-W N or a pharmaceutically acceptable non-toxic salt thereof, wherein X is a heteroaromatic moiety of the formula:

unsubstituted or substituted by chlorine,

Y is phenyl unsubstituted or substituted by alkyl of l to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen, and

Z is phenyl.

2. The compound according to claim 1 wherein X is .C1,

and Z is- 3. The compound according to claim 1 wherein 5. The compound according to claim 1 wherein andzis f 6 A compound the formula {8] gm] -n Y is phenyl unsubstituted or substituted by fluorine, X chlorine, alkyl of l to 4 carbon atoms or alkoxy of l to 4 carbon atoms, and or a pharmaceutically acceptable non-toxic salt Z is phenyL p wherem l0 7. A compound according to claim 6 wherein Y is X is a 6-membered heteroaromatic moiety of the phenyl p chlorophenyl or 0401),].

formula UNITED STATES PATENT OFFICE QERHHCATE ()F CORRECTION PATENTNO: 3,928,348

DATED December 23, 1975 INVENTOR(S) WILFRIED DRABER ET AL It is certified that error appears in the ab0ve-identified patent and that said Letters Patent Q are hereby corrected as shown below:

The structural formula in claims 1 and 6 should be changed from to Y..L N

Signed and Scaled this eighteenth D a y of May 1976 {SEAL} A tresr:

RUTH C. MASON- Arlesting ()jfi'crr C. MARSHALL DANN Commissioner nj'larenls and Trademarks 

1. A COMPOUND OF THE FORMULA:
 2. The compound according to claim 1 wherein
 3. The compound according to claim 1 wherein
 4. The compound according to claim 1 wherein
 5. The compound according to claim 1 wherein
 6. A compound of the formula
 7. A compound according to claim 6 wherein Y is phenyl, p-chlorophenyl or o-tolyl. 